微生物学报  2023, Vol. 63 Issue (4): 1404-1410   DOI: 10.13343/j.cnki.wsxb.20220707.
http://dx.doi.org/10.13343/j.cnki.wsxb.20220707
中国科学院微生物研究所，中国微生物学会

文章信息

宗萱, 李晓飞, 任方哲, 焦新安, 黄金林. 2023
ZONG Xuan, LI Xiaofei, REN Fangzhe, JIAO Xin’an, HUANG Jinlin.
细胞致死性膨胀毒素损伤宿主防御机制研究进展
Cytolethal distending toxin injures host defense mechanism
微生物学报, 63(4): 1404-1410
Acta Microbiologica Sinica, 63(4): 1404-1410

文章历史

收稿日期：2022-09-19
网络出版日期：2022-11-22
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引用本文
宗萱, 李晓飞, 任方哲, 焦新安, 黄金林. 细胞致死性膨胀毒素损伤宿主防御机制研究进展[J]. 微生物学报, 2023, 63(4): 1404-1410.
Zong Xuan, Li Xiaofei, Ren Fangzhe, Jiao Xin’an, Huang Jinlin. Cytolethal distending toxin injures host defense mechanism[J]. Acta Microbiologica Sinica, 2023, 63(4): 1404-1410.
细胞致死性膨胀毒素损伤宿主防御机制研究进展
宗萱1 , 李晓飞2 , 任方哲1 , 焦新安3 , 黄金林1,3     
1. 扬州大学江苏省人兽共患病学重点实验室, 江苏 扬州 225009;
2. 江苏高校动物重要疫病与人兽共患病防控协同创新中心, 江苏 扬州 225009;
3. 农业农村部农产品质量安全生物性危害因子(动物源)控制重点实验室, 江苏 扬州 225009
收稿日期：2022-09-19；接受日期：2022-11-14；网络出版日期：2022-11-22
基金项目：国家自然科学基金(32172939，31872493)；山东省泰山产业领军人才项目(tscy20190113)；扬州大学兽医学学科特区学科交叉课题支持项目(yzuxk202003)
摘要：细胞致死性膨胀毒素(cytolethal distending toxin, CDT)属于AB2毒素，由多种革兰氏阴性菌产生。CDT是第一种被描述的细菌基因毒素，编码3种多肽：CDTA、CDTB和CDTC。CdtB是活性部分，有损伤多种细胞类型的能力。CDT具有一种新的分子作用模式，会干扰真核细胞周期的进展，从而导致G2/M停滞和细胞凋亡，该作用机制针对细胞，而且现阶段对于CDT的研究更多也是细胞层面，但是CDT作为毒力因子最终作用是损伤宿主造成疾病。但目前对CDT与宿主相互作用的分子机制了解尚不清晰。本文对细胞致死性膨胀毒素作为毒力因子从损伤上皮屏障、适应性免疫以及促进炎症反应三方面来综合阐述其对宿主防御机制途径的损伤，以期了解其致病机制以及为其临床治疗提供理论依据和新思路。
关键词：细胞致死性膨胀毒素    细胞膨胀    毒力因子    损伤机制    
Cytolethal distending toxin injures host defense mechanism
ZONG Xuan1 , LI Xiaofei2 , REN Fangzhe1 , JIAO Xin’an3 , HUANG Jinlin1,3     
1. Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu, China;
2. Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China;
3. Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture and Rural Affairs, Yangzhou 225009, Jiangsu, China
Received: 19 September 2022; Accepted: 14 November 2022; Published online: 22 November 2022
*Corresponding author: HUANG Jinlin, Tel: +86-514-87971136, E-mail: jinlin@yzu.edu.cn.
Foundation item: This work was supported by the National Natural Science Foundation of China (32172939, 31872493), the Taishan Industry Leading Talents Project in Shandong Province (tscy20190113), and the Yangzhou University Interdisciplinary Research Foundation for Veterinary Medicine Discipline of Targeted Support (yzuxk202003)
Abstract: Cytolethal distending toxin (CDT) is an AB2 toxin produced by a variety of Gram-negative bacteria. It was the first bacterial genotoxin described, encoding three polypeptides: CDTA, CDTB, and CDTC. CdtB is the active moiety that has the ability to damage multiple cell types. CDT has a new molecular mode of action, which can interfere with the progress of eukaryotic cell cycle, resulting in G2/M arrest and apoptosis. Such mechanism of action targets cells, and the available studies of CDT concentrate on the cellular level. However, CDT, as a virulence factor, ultimately causes pathogenic damage to the host, and the molecular mechanism of CDT-host interaction remains unclear. This paper comprehensively expounded the damage of CDT as a virulence factor to the host defense mechanism from three aspects, including damage to the epithelial barrier, acquired immunity, and promotion of inflammatory response, aiming to reveal the pathogenic mechanism of CDT and provide a theoretical basis and new ideas for clinical treatment.
Keywords: cytolethal distending toxin    cell distention    virulence factors    damage mechanism    

细胞致死性膨胀毒素(cytolethal distending toxin, CDT)由多种革兰氏阴性致病菌产生，例如大肠杆菌(Escherichia coli)[1]，弯曲杆菌属(Campylobacter spp.)[2]，放线菌类(Aggregatibacter actinomycetemcomitans)[3]和杜克雷嗜血杆菌(Hemophilus ducreyi)[4]等。目前已知CDT是一种特殊的细菌毒素[5]，具有核酸酶和磷酸酶两种酶活性，针对两种酶活性，有研究提出2种分子作用模式，一是以宿主DNA作为破坏的靶标，诱导细胞中双链DNA的断裂，从而导致细胞分裂周期中的停滞，从而导致靶细胞死亡[6]；二是作为磷酸酶阻断磷酸肌醇-3-激酶(phosphoinositide-3 kinase, PI-3K)信号通路，影响通路中激酶的磷酸化程度[7]。现阶段对于CDT的研究更多关注的是其对细胞的损伤作用，但是CDT的最终作用是损伤宿主导致疾病。

有文献已经证明了CDT有利于细菌的持久性感染和炎症发生[8]，也有证据表明携带基因毒素的细菌在特定情况下可能有助于肿瘤的发展[9]。CDT作为细菌毒素家族中的一位，有研究进行体内实验，证明CDT可以促进小鼠模型中的结直肠癌变[10-12]。CDT致病的原因之一是其对宿主免疫应答具有影响[13]，免疫应答是所有哺乳动物中针对病原体、毒素和其他抗原的主要防御机制，具有免疫刺激或免疫抑制作用[14]。宿主机体对侵入体内的病原微生物有固有免疫和适应性免疫两种应答方式。CDT损伤细胞后是如何影响宿主的免疫应答防御机制，从而造成宿主长久性炎症的发生，甚至发展成为癌症？本文基于目前对CDT全毒素功能以及作用机制的理解，综述了CDT对免疫应答反应的影响，并且讨论了CDT损伤宿主防御机制途径。

1 破坏上皮屏障

上皮细胞构成宿主生物体与充满微生物的周围环境之间的机械屏障[15]。因此，损伤保护性上皮层会使其下层组织暴露于细菌及其产物中。目前产生CDT的革兰氏阴性菌是对口腔、胃肠道、泌尿和呼吸道等黏膜皮肤组织定殖有亲和力的病原体[16-18]。现阶段研究发现上皮细胞对于CDT高度敏感，容易受到CDT毒性的影响，因此牙龈上皮以及肠道上皮是CDT的靶标，可以引发病理性上皮屏障的变化。

在口腔中，高度增殖的原发性人牙龈上皮细胞(human gum epithelial cells, HGEC)对放线菌产生的CDT毒素敏感，表现出类似于用CDT处理的永生化人口腔前庭上皮细胞系(GMSM-K)出现的形态改变和细胞活力的下降[19]。体外实验表明CDT改变了牙龈上皮屏障的完整性，形态学变化包括角质化外层的脱离，口腔上皮中棘细胞和基底细胞的膨胀，以及细胞连接的明显溶解[20]。CDT还会改变肌动蛋白细胞骨架以及局灶性粘附和微管网络紊乱，导致的肠上皮细胞粘附性降低[21-22]。病原体杜克雷嗜血杆菌(Haemophilus ducres)是导致性传播软下疳(最普遍的生殖器溃疡病)的公认原因[23]，最近已成为太平洋区域和非洲的慢性肢体溃疡(类似于雅司病)的主要病因。

CDT引发病变与其对细胞活性损害、细胞凋亡和细胞坏死有关。细胞凋亡是CDT破坏上皮屏障的主要机制之一，CDT会对不同类型的上皮细胞有凋亡作用。有研究以IEC-6、HT-29作为CDT细胞损伤体外实验的研究对象，暴露于原核表达重构的CDT中，会增加细胞DNA损伤并停滞细胞周期，减少细胞增殖[11]。线粒体凋亡途径可能是CDT诱导细胞凋亡的主要途径。暴露于CDT的INT407细胞，其H2A组蛋白家族成员X (H2A histone family member X, H2AX)发生磷酸化，促凋亡Bax蛋白的表达上调，而Bcl-2的表达降低，细胞色素c从线粒体中释放出来，半胱天冬酶3/7和半胱天冬酶9被激活[24]。这表明CDT在造成细胞损伤后可以诱导线粒体凋亡途径。CDT通过改变上皮细胞的生长和活力来破坏上皮屏障从而促进感染。

2 促进炎症反应

先天免疫是宿主抵御微生物病原体的第一道防线。中性粒细胞、NK/NKT细胞、单核细胞/巨噬细胞和树突状细胞与病原体相互作用，这形成先天免疫系统的一部分，在感染和组织损伤的初始免疫反应中起关键作用。各种研究表明CDT靶向这类细胞，因此涉及到许多相关疾病的持续感染以及强烈的炎症反应。

暴露于放线菌CDT的小鼠巨噬细胞的吞噬作用显著下降[25]，并且有研究证明了放线菌CDT可以激活NLRP3炎症小体，诱导了巨噬细胞的炎症反应[26]。牙周炎(laparoscopic, LAP)与放线菌CDT引起的感染有关，对LAP发病机制的实验和临床研究表明，牙周内存在高水平促进炎症的细胞因子。此外，有研究提出，组织的炎症会产生降解的蛋白质和血红素，这有助于促进细菌的营养需求，从而促进细菌的生长和存活，并进一步加剧炎症[27]。

炎症反应的机制主要是阻断PI-3K信号通路[7]。已经证明CDT可以扰乱来自人髓系白血病单核细胞(human myeloid leukemia mononuclear cells, THP-1)细胞系的人单核细胞和巨噬细胞中的PI-3K信号传导[28]。暴露在CDT之中会降低Akt和糖原合成酶激酶3β (GSK3β)磷酸化程度，有研究检测到下游激酶活性的改变。单核细胞和巨噬细胞暴露于CDT导致促进炎症细胞因子产生，包括白细胞介素1β (IL-1β)、肿瘤坏死因子(tumor necrosis factor, TNF)和白细胞介素6 (interleukin 6, IL-6)的表达和释放增加[29]。CDT可能通过损害巨噬细胞的活性和吞噬作用以及改变促炎/抗炎细胞因子的平衡导致组织损伤。

3 抑制适应性免疫

适应性免疫是指体内抗原特异性T/B淋巴细胞接受抗原刺激后，自身活化、增殖、分化为效应细胞，产生一系列生物学效应的全过程[30]。适应性免疫能识别特定病原微生物(抗原)或生物分子，最终将其清除。适应性免疫在识别自我、排除异己中起了重要作用。与其他类型的细胞相比，淋巴细胞(B细胞和T细胞)对CDT中毒表现出高敏感性，因此CDT会产生对适应性免疫的抑制作用。

对放线菌CDT以及来自杜克雷嗜血杆菌的CDT研究表明，在携带相应病原体的局部侵袭性牙周炎(LAP)或软下疳患者中，抗CDT反应产生低水平的抗体[31]。此外，在检测到抗体的大多数情况下，CDT中和抗体的发生率和效力都很低[32]。因此研究中和抗体效应的作者得出结论，异三聚体全毒素是非免疫原性的，或者它阻碍了宿主细胞对免疫原作出反应的能力[33]。有研究用CDT制备的类毒素对兔子进行免疫会导致能够中和毒素的强大免疫反应；本课题组制备了CdtB和CdtC单抗[34]；也有研究对大鼠模型进行CdtB的皮下注射，在血清中检测到了抗体，这支持了CDT作为免疫毒素功能的观点[35-37]。大量研究表明，CDT在恶性T细胞系中迅速触发细胞周期G2期的短暂停滞，随后是细胞死亡(通常在24 h内)，Shenker等用低浓度的放线菌CDT处理人Jurkat细胞(外周血白血病T细胞)和有丝分裂原激活的人外周血巨噬细胞(human peripheral blood macrophages, HPBMC)，观察到其增殖被抑制以及细胞周期的停滞[38]，而Nalbant等用相同剂量的缺失CdtB亚基的突变体处理细胞则没有观察到这种抑制作用[39]。同样，Gelfanova等证明，杜克雷嗜血杆菌CDT也抑制了相同细胞群的增殖并诱导了细胞凋亡[4]。Xu等还证明，用杜克雷嗜血杆菌CDT处理的单核细胞衍生的树突状细胞不表现出细胞因子反应并且抑制T细胞增殖[40]。

CDT通过损伤DNA和激活细胞周期检查点将细胞周期阻断在G2/M期(也可在G1期)，从而使细胞发生程序性死亡。控制细胞从G2期进入有丝分裂M期的2个主要蛋白是细胞周期蛋白B1和细胞分裂周期2蛋白(Cdc2)。CDT作用细胞时，CdtB具有脱氧核糖核酸酶活性使DNA降解，阻断Cdc2的细胞周期依赖性脱磷酸作用，导致有丝分裂不能正常进行，造成细胞周期阻滞[41]。并且有研究推测，活性Cdc2的减少是由于G2细胞周期检查点级联的激活，这阻止了细胞复制[42]。所以这种毒素不仅会抑制淋巴细胞的增殖和存活，而且还可能干扰免疫反应的早期阶段[43]。

4 展望

现阶段研究已经探索了CDT功能作用机制，其针对细胞造成损伤，以及其与各种疾病相关联性，其中大多数说明了这种特殊细菌基因毒素的促炎性质，本文论述了CDT作为毒力因子通过诱导上皮细胞死亡来破坏结构屏障，以及通过影响淋巴细胞来损伤获得性免疫，此种方式靶向宿主的防御机制。目前损伤细胞的作用机制与宿主病变之间的关系依旧不清楚。现阶段已知细胞对CDT的敏感性存在差异，但是这种差异敏感性是否与毒素分子作用机制直接相关也是未知的，并且差异敏感性直接导致表现出的病症不同。由于体内感染模型的缺少以及相关技术的限制，导致CDT损伤细胞与宿主之间的相互作用关系还有待深入。随着体内感染技术以及相关细胞模型的发展，对CDT致癌特性的研究越来越有前景。

目前对致癌的认识是片面的以及带有推测性的，毒素作用与细胞内递送之间的直接联系及其临床相关性在很大程度上仍不清楚。一方面研究产生CDT的细菌的长期持续感染是否与宿主癌症进展风险增加有关；另一方面细菌产生的可自然引起体内肿瘤发生的基因毒素的浓度尚不清楚。多种革兰氏阴性菌都能产生CDT，但是不同细菌物种产生的CDT损伤细胞的分子机制和细胞内运输途径仍然有待研究。因此对于细胞致死性膨胀毒素详细作用机制研究是至关重要的，继续深入了解全毒素与宿主相互作用将为进一步研究细胞致死性膨胀毒素的调控机制提供新思路，为解析毒素与癌症致病机理的关系提供依据。

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细胞致死性膨胀毒素损伤宿主防御机制研究进展
宗萱 , 李晓飞 , 任方哲 , 焦新安 , 黄金林